Pharmaco: Paracetamol + Opioids Flashcards
[Paracetamol]
MOA
- CNS-selective cox inhibition
- Modulates how the brain interprets pain signals
No anti-inflammatory properties as it does not inhibit COX at the site of injury/inflammation
[Paracetamol]
Indication
Mild-mod pain, when NSAIDs are inappropriate
[Paracetamol]
Advantages
- good analgesic
- potent antipyretic
- spares the GI tract (no COX inhibition in the stomach)
- side effects are few and uncommon
- few DDIs
- safe for pediatric use - pediatric formulations
[Paracetamol]
Disadvantages
- weak anti-inflammatory
- toxic doses cause nausea and vomiting, liver damage (esp in overdose, or chronic alcohol abuse)
- allergic skin reactions may occur
[Paracetamol]
Explain the mechanism of liver damage with overdose of paracetamol
Paracetamol metabolism is rapid and wears off within 12h
Major pathway (phase 2 glucuronidation and sulfation) into non-toxic glucuronide and sulfate metabolites that are excreted
Minor pathway (CYP450 2E1) into highly reactive intermediate NAPQI metabolite (quinone imine)
Under normal circumstances, NAPQI is quickly conjugated with nucleophilic glutathione (GSH) via Michael addition reaction and excreted as non-toxic cysteine and mercapturic acid conjugates.
In overdose, the major glucuronidation and sulfation pathways get saturated, resulting in a more acetaminophen undergoing the minor pathway and getting oxidized to NAPQI.
The high concentrations of NAPQI metabolites formed from the oxidation by CYP2E1 depletes GSH stores, leading to insufficient GSH to quench it.
As such, excess NAPQI is able to react with nucleophilic hepatic macromolecules leading to the formation of adducts (NAPQI-protein). For instance, it can form mitochondrial protein adducts and confer mitochondrial damage. It may also form adducts that can evoke immunogenic reactions or abolish enzyme activity.
As a result, there is acute liver tissue damage and potential liver failure (acute hepatotoxicity/ drug-induced liver injury).
[Paracetamol]
How does chronic alcoholism play a role in the mechanism of liver damage with paracetamol?
Alcohol induces CYP2E1 and hence more paracetamol undergoes minor pathway into the reactive NAPQI
Alcohol depletes glutathione levels
[Paracetamol]
How can GSH be replenished in event of overdose?
N-acetyl-cysteine (NAC)
*Methionine - onset is shorter
*Glutathione - poor bioavailability
[Paracetamol]
Use with caution in:
- Hepatic dysfunction
- Alcohol abuse
[Paracetamol]
Which populations may require dose reduction?
- Underweight, cachectic, frail
- Significant liver disease
[Paracetamol]
What doses may lead to increased risk of liver damage, and when should patient be referred to ED?
Usual dose: 500mg-1g q4-6h; max 4g in 24h
Increased risk of harm with doses exceeding 4g per 24h (narrow therapeutic window to liver toxicity)
Refer to ED if taken >=10g in 24h (20 tablets)
Also note that paracetamol has an analgesic ceiling, above 1g per dose there would have been no additional analgesia
[Paracetamol]
S&S of liver damage to look out for:
- Nausea, sudden weight loss, loss of appetite
- Yellowing of eyes and skin
- Unexplained bruising or bleeding
[Paracetamol]
Interactions
- Alcohol – can increase risk of liver damage
- Warfarin – limit paracetamol to 2g/day as paracetamol may enhance the effect of warfarin, can alter INR levels (possibly increase)
[Paracetamol + NSAID combination]
Analgesic vs Antipyretic effect
Take Paracetamol + Ibuprofen tgt (both dosed q4-6h)
- Synergistic effect: stronger for longer analgesia effect
Take alternating Paracetamol + Ibuprofen
- Sustained antipyretic effect
[Opioids]
MOA
Blocks transmission and signaling of pain through the nerves at the spinothalamic relay and the CNS
(Inhibit ascending pain pathway)
[Opioids]
Weak –> Strong
Weak: Tramadol, Codeine
Strong: Morphine, Oxycodone, Fentanyl
[Opioids]
Indication and why
NOT 1st line for pain
NOT anti-inflammatory
Stronger analgesic effect than paracetamol and NSAID, may use to control severe pain
Note that: tramadol can be combined with paracetamol (acugesic), codeine with paracetamol (panadeine), but opioids not commonly combined with NSAIDs
However, significant risk for adverse effects, diversion, misuse
[Opioids]
How should opioids be used?
Lowest effective dose of weakest effective opioid for the shortest duration
Ensure pt is educated on use, storage, risk of adverse effects, abuse potential
[Opioids]
Response to opioids may be variable due to
Polymorphism in CYP2D6 metabolising enzyme (from 0-15% of codeine to the more potent morphine)
[Opioids]
With greater potency, there is greater _____
Analgesic effect but also undesired adverse effects
[Opioids]
Why might tramadol be used in chronic pain?
Tramadol MOA:
1st MOA: Tramadol and M1 binds to opiate receptors that mediate ascending pain pathways → inhibit them
2nd MOA: Tramadol and M1 inhibit the reuptake of NE and 5-HT → Increase availability of NE and 5-HT → greater activation of descending pain pathways
Use in chronic pain:
Tramadol has additional NE and 5-HT reuptake inhibition effects, helps with analgesic effects particularly in chronic and neuropathic pain
However, also risks serotonin syndrome when used with serotonergic agents
[Opioids]
Adverse effects
- GI effects (constipation, nausea, vomiting)
- Hormonal effects (imbalance in hormones)
- Dermatologic: dermatitis, pruritus, skin rash
- CVS: chest pain, flushing, hypertension, peripheral edema, vasodilation
- Anticholinergic: dry mouth (xerostomia), urinary retention
- CNS: Sedation/drowsiness => falls, fractures
- Respiratory: bronchitis, cough, dyspnea
Serious ADRs:
- CNS depression (excessive sedation, dcr cognitive function)
- Respiratory depression (slowed breathing) - higher dose
- Overdose, coma and death - higher dose
- Tolerance, physical dependence, addiction, withdrawal
- Opioid-induced hyperalgesia (paradoxically worsen pain)
- Serotonin syndrome (Tramadol, Fentanyl, Pethidine)
- Hyponatremia
- Seizures
High risk of adverse effects, 80% of pt on long-term opioids will develop at least one of these)
with regards to constipation, pt may take senna/lactulose to prevent or manage
with regard to drowsiness, avoid driving
[Opioids]
Risk factors for opioids use
- Combi with other CNS depressants (alcohol, BZDs, gabapentinoids, antidepressants)
- Other comorbidities (e.g., mental health conditions)
- Renal or hepatic insufficiency, age >65y (think risk of falls and fractures)
- Pregnancy (risk to both mother and fetus)
- Personal or family history of substance use disorder
- Already prescribed an opioid (incr risk w incr dose and duration of use; risk of diversion; risk of opioid use disorder)
[Tramadol]
Contraindications
- Hypersensitivity
- Pt <12y
- Significant respi depression
- Concomitant/within 14d of MAOi
- Acute/severe bronchial asthma in absence of monitoring/resuscitative equipment
- GI obstruction (e.g., paralytic ileus)
- Pediatric pt <18y of age who underwent tonsillectomy/adenoidectomy (e.g., sleep-disordered breathing following tonsillectomy)
[Opioids]
Discontinuation
Risk of withdrawal symptoms: anxiety, insomnia, sweating, rigors, pain, tremors, nausea, diarrhea
To combat,
Gradually tapering dose (individualize tapering)
Monitor withdrawal symptoms
- Fast onset: within 24h
- Resolves in 2-7 days
[Tramadol]
Special populations:
- renal impairment
- hepatic impairment
- elderly
- pregnancy
- breastfeeding
Usual dose for acute pain: 25-50mg TDS PRN => 50-100mg q4-6h, max 400mg/day for max 7 days
- renal impairment: CrCl <30ml/min - increase dosing interval to q12h, max 200mg/day; CrCl <10ml/min - 50mg q12h
- hepatic impairment: child pugh class C - avoid use/50mg q12h (avoid in severe hepatic impairment due to reduced efficacy and clearance)
- elderly: >75y, max 300mg/day, initiate at lower end of dosing range
- pregnancy: do not give
- breastfeeding: do not give
